AMP activated protein kinase (AMPK), which maintains normal energy balance by regulating cellular metabolisms in an AMP/ADP ratio-dependent manner, is critically responsible for the proper mechanistic modulation of autophagy. During cellular starvation, AMPK induces autophagy by phosphorylating Ulk1, the mammalian counterpart of ATG1, at Ser 317 and 777. Molecular studies demonstrated that Ulk1 together with another mammalian ATG1 homolog Ulk2 interacted with mATG13 and FIP200 (mammalian homologues of ATG13 and ATG17) to form complex and regulate the autophagic machinery. Extensive genetic studies using yeast models have also suggested the inductive role of ATG1 kinase in autophagy. Conversely, under nutrient-rich conditions, the activation of mTOR prevents the phosphorylation of Ulk1 activation through Ser 757, which finally inhibits the Ulk1-AMPK regulated induction of autophagy. Besides, AMPK stimulates autophagy through the inhibition of mTORC1, which is the key regulator of growth factor and nutrient signals transduction.
In fact, autophagy may play its anti-cancer role by preventing accumulation of damaged proteins and organelles which leads to the progression of tumor growth, or via the induction of autophagic cell death. However, some studies show that AMPK activator may also stimulate cell grow under some circumstances. Therefore, identification of novel AMPK activator for the induction of autophagy has been a new approach for new cancer drug discovery.